CN114555560A

CN114555560A - Menthol derivatives and uses thereof

Info

Publication number: CN114555560A
Application number: CN202080069090.3A
Authority: CN
Inventors: D·A·克伦普; R·A·克伦普; Z·利韦里斯; M·斯坦策尔; R·M·索贝尔; S·G·科基尼杜
Original assignee: Funa Technology Co ltd; Northern Illinois University
Current assignee: Funa Technology Co ltd; Northern Illinois University
Priority date: 2019-09-30
Filing date: 2020-09-29
Publication date: 2022-05-27
Also published as: US20210093531A1; MX2022003764A; EP4038048A1; CA3152574A1; WO2021067301A1; US20240074958A1; WO2021067301A8

Abstract

A compound comprising menthyl glycinate. The menthyl glycinate comprises menthol linked to glycine or a glycine derivative through an ester linkage. The radical on the N atom being denoted R₁And R₂，R₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring. R₁And R₂Each containing up to 20 carbon atoms.

Description

Menthol derivatives and uses thereof

Background

Natural menthol is known as an agent that provides a cooling sensation ("cooling agent"), and has been used for many years as an ingredient in various consumer products, such as candies and gums, toothpastes, mouthwashes, shaving creams, and skin creams. The ability of menthol to chemically trigger the cold sensitive TRPM8 receptor is responsible for its well known cooling sensation when inhaled, consumed or spread on the skin. TRPM8 is an ion channel that, when activated, allows Na⁺And Ca²⁺Ions enter the cell, resulting in depolarization and the generation of action potentials. The application of menthol to the skin or mucosa directly leads to membrane depolarization followed by calcium influx through voltage-dependent calcium channels, which provides evidence for the role of TRPM8 and other TRP receptors in mediating our sensory interactions with the environment in the same way as they respond to menthol in response to cold. The cooling (eating) threshold for (-) -menthol in the flavor dilution test was 0.8 ppm.

Chemical structure of (-) -menthol

For decades, there has been interest in the preparation of organic compounds that can match or exceed the perceived cooling sensation of menthol. Most notably, a series of Wilkinson Sword (WS) compounds have been developed, some of which have been used in consumer products. Since these developments in the 1970 s, a variety of other cooling agents have been proposed and developed — some of which exceed the cooling potential of menthol by >200 times. Several cooling agents are known which have a carboxyl group attached to menthol, such as WS-3, WS-5, WS-12, Frescolat ML and Compound 1 (which is expected to be about 1000 times cooler than menthol).

Chinese patent application (CN 1915966) describes the use of menthol derivatives N, N-dimethylglycine menthyl ester, N-diethylglycine menthyl ester and N, N-dihydroxyethylglycine menthyl ester as transdermal agents to facilitate the subcutaneous absorption of transdermal formulations. The chinese application describes the use of these menthol derivatives in ointments, creams, patches, pharmaceuticals and cosmetics.

Disclosure of Invention

In a first aspect, the present application describes compounds of formula (I):

wherein R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring. R ₁And R₂Each containing up to 20 carbon atoms and the compound is not N, N-dimethylglycin menthyl ester, N-diethylglycin menthyl ester or N, N-dihydroxyethylglycin menthyl ester.

In a second aspect, the present application describes a method of providing a cooling sensation in an oral cavity, comprising: a cooling agent for oral administration, wherein the cooling agent is of formula (I).

Wherein R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, and R₁And R₂Each containing up to 20 carbon atoms.

In a third aspect, the present application describes a method for preparing menthyl glycinate. The process comprises reacting menthol with bromoacetyl bromide or chloroacetyl chloride to form an ester, separating the ester, and reacting the ester with an amine to form menthyl glycinate.

In a fourth aspect, the present application describes an oral hygiene product or an edible product comprising: a compound of formula (I).

And a solvent or carrier, wherein R₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, and R₁And R₂Each containing up to 20 carbon atoms.

In a fifth aspect, the present application describes an insect repellent comprising: the formula (I).

And a carrier. R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, and R₁And R₂Each containing up to 20 carbon atoms.

In a sixth aspect, the present application includes a compound comprising: a compound of the formula (II),

or formula (III).

Wherein R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, and R₁And R₂Each containing up to 20 carbon atoms, and L is alkylene, arylene, - (CH)₂)_X-(OCH₂CH₂)_nO-(CH₂)_X- (wherein x and n are independently 1 to 10 and x + n is at most 10) or

(wherein R is₁And R₂Each independently selected from H and OH, and a and b are independently 0, 1, 2 or 3), wherein the L group has up to 20 carbon atoms.

Definition of

Aromatic ring or aryl means a monovalent aromatic carbocyclic group or heteroaryl group, preferably having 3 to 10 carbon atoms. The aromatic ring or aryl group may be monocyclic (e.g., phenyl (or Ph)) or polycyclic (e.g., naphthyl), and may be unsubstituted or substituted. Preferred aryl groups include phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl, quinolinyl, or isoquinolinyl.

Alkyl (or alkyl-or alk-) means a monovalent, substituted or unsubstituted, saturated or unsaturated, linear, branched or cyclic hydrocarbon chain, preferably containing from 1 to 20 carbon atoms. More preferred alkyl groups are alkyl groups containing 7 to 16 carbon atoms. Preferred cycloalkyl groups have 3 to 10 (preferably 3 to 6) carbon atoms in their ring structure. Suitable examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, sec-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl and cyclohexyl. The alkylaryl group and the alkylheterocyclyl group are alkyl groups covalently bonded to an aryl or heterocyclyl group, respectively. Unsaturated alkyl refers to an alkyl group containing one or more double and/or triple bonds.

By "substituted" is meant that the moiety contains at least one (preferably 1-3) substituent. Suitable substituents include hydroxy (-OH), amino (-NH)₂) Oxy (-O-), carbonyl (-CO-), thiol (-SH), alkyl, alkoxy (-OR), halogen, nitrile (-OR), nitro (-OR), aryl and heterocyclic groups. These substituents may optionally be further substituted with 1-3 substituents. Examples of substituted substituents include formamide, alkylmercapto, alkylsulfonyl, alkylamino, dialkylamino, carboxylate, alkoxycarbonyl, alkylaryl, arylalkyl, alkylheterocycle, and the like.

Arylene group means a divalent aromatic carbocyclic or heteroaromatic group, preferably having 3 to 10 carbon atoms. The arylene group can be monocyclic (e.g., phenylene (or Ph)) or polycyclic (e.g., naphthylene), and can be unsubstituted or substituted. Preferred arylene groups include phenylene, naphthylene, furanylene, thiophenylene, pyridinylene, indolyl, quinolinylene, or isoquinolinylene.

Alkylene means a divalent, substituted or unsubstituted, saturated or unsaturated, linear, branched or cyclic hydrocarbon chain, preferably containing from 1 to 20 carbon atoms. More preferred alkylene groups are alkylene groups containing from 7 to 16 carbon atoms. Preferred cycloalkylene groups have 3 to 10 (preferably 3 to 6) carbon atoms in their ring structure. Suitable examples of unsubstituted alkylene groups include methylene, ethylene, propylene, isopropylene, cyclopropylene, butylene, isobutylene, tert-butylene, sec-butylene, cyclobutyl, pentylene, cyclopentylene, hexylene, and cyclohexylene.

Drawings

FIG. 1 IS a graph showing the average area ratio (Comp./IS) of XI-1-60 and menthol in ethanol measured at initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 2 IS a graph showing the average area ratio (Comp./IS) of XI-1-60 and menthol in Propylene Glycol (PG) measured at the initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 3 IS a graph showing the average area ratio (Comp./IS) of XI-1-60 and menthol in water measured at initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 4 IS a graph showing the average area ratio (Comp./IS) of XI-1-50 and menthol in ethanol measured at initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 5 IS a graph showing the average area ratio (Comp./IS) of XI-1-50 and menthol in PG measured at initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 6 IS a graph showing the average area ratio (Comp./IS) of XI-1-50 and menthol in water measured at initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

FIG. 7 IS a graph showing the average area ratio of RK-2-10 and menthol in ethanol (Comp./IS) measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

FIG. 8 IS a graph showing the average area ratio (Comp./IS) of RK-2-10 and menthol in PG measured at the initial time, after 24 hours, after 48 hours, after 1 week, and after 2 weeks.

FIG. 9 IS a graph showing the average area ratio in water of RK-2-10 and menthol (Comp./IS) measured at the initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

Fig. 10 IS a graph showing the average area ratio (comp./IS) of menthol in ethanol measured at the initial time, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

Figure 11 is a graph showing the time versus intensity of cooling sensation for menthol and various menthyl glycinates in lozenges.

Figure 12 is a graph showing the time versus intensity of cooling sensations for menthol and various menthyl glycinates in a beverage model system.

Figure 13 is a graph showing the time versus intensity of cooling sensations for menthol and various menthyl glycinates in mouthwash.

Detailed Description

Menthyl glycinate, its use as a cooling agent and a process for the preparation of menthyl glycinate are described. A large amount of experimental data in this application is published in Klumpp, DA et al, "Synthesis of Menthol carbohydrates and Their Potential as coating Agents", ACS Omega, vol.5, No.8, pp.4043-4049 (2020). Preferably, the menthyl glycinate is an ester comprising menthol linked via an ester bond to glycine or a glycine derivative. These menthyl glycinates are very suitable for providing a long lasting cooling effect and are used as flavouring agents in food products. Esters hydrolyze at a slow rate in an aqueous environment, providing slow release of menthol and glycine or glycine derivatives. As the hydrolysis proceeds, more menthol may act on the TRPM8 receptor, providing a cooling effect for a longer period of time. These compounds may also provide a delay in the onset of cooling. Taste tests have shown that these menthyl glycinates provide a long lasting cooling effect at the lowest concentration, far exceeding that of menthol itself. In addition, glycine provides sweetness and acts as a flavoring agent, and it is believed that glycine enhances the cooling sensation of menthol. The amine functionality of glycine can impart good solubility characteristics to menthyl glycinate, making these compounds easier to include in various food products. The menthyl glycinate has the following formulas (I), (II) and (III).

Formula (I) includes a menthol group attached to a glycine derivative via an ester linkage. The menthyl glycinate may also be referred to as menthol glycinate. Formulas (II) and (III) illustrate a menthyl glycinate ester, which includes two menthol groups. R₁And R₂May independently be hydrogen or an alkyl group. R₁And R₂Each containing up to 20 carbon atoms. R₁And R₂May be different or the same. R₁And R₂It is also possible to form a ring with the nitrogen as part of the ring. The ring may be, for example, a 4, 5, 6, 7 or 8 membered ring.

R₁And R₂Examples of (b) include methyl, ethyl, propyl, butyl, cyclopropyl, ethyl methyl ether, isopentyl, benzyl, isopropyl, isobutyl, tert-butyl, and ethylpyridine. Wherein R is₁And R₂Examples of the ring containing a nitrogen atom include a pyrrolidine ring and a piperidine ring.

The L group in formula (III) is alkylene, arylene, - (CH)₂)_X-(OCH₂CH₂)_nO-(CH₂)_X- (wherein x and n are independently 1 to 10 and x + n is at most 10) or

(wherein R is₁And R₂Each independently selected from H and OH, and a and b are independently 0, 1, 2 or 3), wherein the L group has up to 20 carbon atoms. Examples of L include (CH)₂)_XWherein X is 1 to 20, for example methylene, (CH)₂)₂、

(CH₂)₃、(CH₂)₄、(CH₂)(CH)(CH₃) And (CH)₂)(CH₂))(CH)(CH₃)。

The process for producing the desired menthyl glycinate ester comprises first reacting menthol with bromoacetyl bromide or a similar acid bromide, and then reacting the product with an amine to form the compound of interest. Bromides can be readily substituted with a variety of amines, including ammonia. Chloroacetyl chloride can also be used to react with menthol to produce the ester of chloroacetic acid. The substituents on the amino group can be prepared by simple substitution chemistry. Scheme 1 below illustrates the first step of reacting menthol with bromoacetyl bromide to form product 2. Product 2 can then be reacted with various amines to produce the desired product.

Scheme 1

Various menthyl glycinates may be prepared from esters and amines of bromoacetic acid. It has been found that secondary amines generally give the desired substituted products in good yields. Most conversions will reach 100% if a slight excess of amine is used.

Menthyl glycinate has the same or similar uses as menthol and provides a similar cooling sensation. The menthyl glycinate ester can be contained in toothpaste, mouthwash, candy, chewing gum, mint, skin cream, aftershave, smoking product, insect repellent, and flavoring and perfume. The menthyl glycinate can be used for providing a cooling sensation, providing a flavoring agent, relieving minor sore throat or minor oral or throat irritation, reducing skin itching, relieving minor pain and distress, treating sunburn, treating halitosis, and as a floral fragrance.

The menthyl glycinate ester may be included in a formulation with a solvent or carrier to dissolve, dilute, load, disperse or deliver the menthyl glycinate ester. Such solvents or carriers include water, castor oil, citric acid esters of mono-and diglycerides, ethyl acetate, glycerol (glycerin), diacetin, isopropanol, mono-and diglycerides, and propylene glycol mono-and diesters of fatty acids. For example, chewing gum comprising menthyl glycinate may also contain gum base, sugar, plasticizers, flavoring agents, colors and/or polyols. The insect repellent may comprise water, glyceryl stearate, beeswax, vegetable glycerin, xanthan gum, potassium sorbate and/or citric acid.

The effective concentration of menthyl glycinate described herein may be determined by routine experimentation. For example, a concentration step may be used to determine the concentration needed to achieve a desired result. Different applications may require different concentrations to achieve the desired effect. When menthyl glycinate is used as a flavoring agent, the concentration may be, for example, 1000ppm to 0.1 ppm. Preferred concentrations are 100 to 0.5ppm, including 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.9, 0.8, 0.7 and 0.6 ppm.

Examples

Chemical and material synthesis

Bromoacetate (compound 2 below) was prepared from menthol and bromoacetyl bromide in quantitative yield, optionally using sodium carbonate as base. Methylene chloride may be used as the solvent, however, other solvents may also be used. Isolation of the product involved simple filtration of the solution (to remove sodium bicarbonate) and evaporation of the solvent under reduced pressure (scheme 1). Compound 2 is very suitable for further synthetic processing because the bromomethyl group is reactive to substitution.

Scheme 1

A series of menthyl glycinates have been prepared from bromoacetate (see scheme 2 and scheme 3). It has been found that primary and secondary amines generally give the desired substituted products in good yields. The optimized operation with diethylamine provided 95% conversion to compound 3 with a small amount of unreacted bromide 2. NMR and GC-FID showed compound 3 to be at least 99% pure. Other secondary amines provided the desired substitution products (

compounds

4, 5 and 6). Most conversions will reach 100% if a slight excess of amine is used. Primary amine (isopropylamine) was used to provide Compound 7(DK-2-39 and DK-1-60 are alternative compound names as Compound 7 in the research record references). The chemical reaction can also be accomplished using methylene chloride or diethyl ether as the solvent and sodium carbonate or sodium hydroxide as the base.

Scheme 2

Scheme 3

A synthetic method has been developed that produces compound 4 in high yield using only filtration and solvent removal in post-reaction processing. Product purification was performed using vacuum distillation. Distillation of compound 4 effectively removed any unreacted starting materials dimethylamine and bromo ester (compound 2). Ease of distillation will facilitate large-scale synthesis of a purified amino ester product.

Various secondary amines provide the corresponding menthyl glycinates. This included dialkylamines which gave

products

3, 6, 9, 10, 15 and 16 (see table 1 below). Heterocyclic systems, such as pyrrolidine and piperidine, have also been found to give substitution products (11 and 5, respectively) in good yields. The primary amines also give the desired

substitution products

7, 12, 14 and 17. The synthesis method is applicable to binding structural components such as cycloalkyl groups, benzyl groups, ethers, and heterocycles. In the case of pyridyl derivative 18, the compound is modeled on the known cooling agent amide 19(FEMA 4549), which is expected to be about 100-fold cooler than menthol.

Table 1: product and yield of substitution reaction of compound 1 with amine or ammonia.

In addition to mono-substitution, the products may also be prepared by di-substitution reactions. When an excess of compound 2 is used, the isopropylamine reacts twice and the product 20 is isolated. Similarly, N' -dimethylethylenediamine is reacted twice with the compound 2 to obtain the product 21. Both 20 and 21 were purified by distillation to remove excess compound 2 and then purified using silica gel chromatography.

Table 2: disubstituted products

For most of the substitution reactions described above, the optimum procedure involves the use of an excess of amine nucleophile. The pure menthyl glycine product was isolated by removing the ethyl acetate solvent and excess amine under reduced pressure. The menthyl glycinate product is then distilled, typically at 150 ℃ and 220 ℃ at 1mm Hg. Optimization studies indicate that excess amine enables the substitution chemistry to be completed in a relatively short time. For example, dibutylamine reacts with product 2 of scheme 1 to provide product 10, with 1.1 equivalents of amine, the substitution reaction is only 79% complete after 3 hours. If the amount of dibutylamine is increased to 1.6 equivalents (0.13M in ethyl acetate), the substitution reaction is 100% complete in less than 3 hours.

Preparation of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl-2-bromoacetate (Compound 2).

(L) -menthol (7.2g, 0.046mmol) was dissolved in 100mL CH₂Cl₂Is neutralized and addedAnhydrous Na₂CO₃. The resulting solution was cooled to 0 ℃ and the flask was charged with CaCl₂And (7) drying the tube. Bromoacetyl bromide (4.0mL, 0.046mol) was then added, the cooling bath was removed, and the solution was stirred for at least four hours. After the reaction period, the solution was filtered through glass wool and the solvent was removed by vacuum. The product was isolated as a clear colorless oil (12.2g, 0.044mol, 96%). Analysis of the crude product by GC-FID and NMR showed very high purity, however, the oil could be further refined by distillation (about 120 ℃ C., 2 mm). By repeated implementation, the yield of crude product varied between 95-100%. ¹H NMR(300MHz,CDCl₃)δ,0.78(d,3H,J＝6.9Hz),0.84-0.96(m,7H),0.96-1.14(m,2H),1.40-1.58(m,2H),1.64-1.74(m,2H),1.88-1.97(m,1H),1.98-2.07(m,1H),3.80-3.82(m,2H),4.70-4.79(m,1H)。13C NMR(75MHz,CDCl₃) δ,16.2,20.7,22.0,23.3,26.1,26.3,31.4,34.1,40.5,46.9,76.5,166.9. Low resolution MS (electron bombardment): 197(M-80),141,139,138(100),123,109.

General procedure for the synthesis of menthyl glycinate (1 ℃ amine).

The amine (0.02mmol) was dissolved in 25mL EtOAc, followed by the addition of NaOH (0.6g, 15mmol) and anhydrous sodium sulfate (0.5g, 3.5 mmol). To this solution was slowly added (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (compound 2, 1.68g, 6.06 mmol). The mixture was stirred for 6 hours or until GC-FID analysis showed no remaining bromo ester (2). The solution was then filtered through a glass wool plug and the solvent was removed by reduced pressure. For low boiling amines, the excess amine is removed in this step. For the less volatile amines, fractional distillation may be required. The final purification of menthyl glycinate is achieved by vacuum distillation.

General procedure for the synthesis of menthyl glycinate (2 ° amine).

(1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (compound 2, 1.68g, 6.06mmol) was dissolved in 25mL EtOAc. To this solution was added amine (9mmol) followed by NaOH (0.6g, 15mmol) and anhydrous sodium sulfate (0.5g, 3.5 mmol). The mixture was stirred for 6 hours or until GC-FID analysis showed no remaining bromo ester (2). The solution was then filtered through a glass wool plug and the solvent was removed by reduced pressure. For low boiling amines, the excess amine is removed in this step. For the less volatile amines, fractional distillation may be required. The final purification of menthyl glycinate is achieved by vacuum distillation.

Product 4- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (dimethylamino) acetate

Using the general procedure with 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with dimethylamine (2.0M in THF) to provide menthyl glycinate 4 in 86% yield as a clear oil (boiling point at 1mm about 140 ℃).¹H NMR(300MHz,CDCl₃)δ,0.36-0.42(m,2H),0.42-0.48(m,2H),0.78(d,3H,J＝7.0Hz),0.85-0.90(m,6H),0.96-1.13(m,2H),1.34-1.44(m,1H),1.46-1.57(m,1H),1.67-1.73(m,2H),1.82-1.90(m,1H),1.97-2.04(m,1H),2.20-2.26(m,1H),2.40(bs,1H),3.34-3.42(m,2H),4.71-4.76(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.2,20.7,22.0,23.3,26.3,31.4,34.2,40.9,45.1,46.9,60.5,74.6,169.9 low resolution MS (electron bombardment ionization): 241(M +),226,138,123,102.

Product 8- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-aminoacetate

In a deep three-neck flask, about 1.5mL (0.064mol) of anhydrous ammonia was condensed at-78 ℃ and then 7mL of EtOAc was added. To this solution was added NaOH (0.6g, 15mmol) and then a solution of (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) in EtOAc (1.51g, 5.5mmol in 7mL EtOAc) was added dropwise. The solution was stirred at-60 ℃ for 2 hours, then warmed to room temperature and excess ammonia was distilled off. The resulting solution was then filtered through glass wool and the solvent removed under reduced pressure to give crude product 8 as an oil. The spectral data are consistent with previously published data.

Product 8 can be prepared by an alternative procedure as described below. Ammonia (about 2mL, 80mmol) was condensed in a cooled (-78 deg.C) round bottom flask and NaOH (0.5g, 12.5mmol) was added to the flask. An addition funnel was attached to the flask. Menthyl bromoacetate (compound 2, 1.4g, 5.0mmol) was dissolved in 10mL ethyl acetate and the solution was placed in the addition funnel. The solution of 2 was then slowly added to the liquid ammonia. The resulting mixture was stirred at-30 ℃ and monitored by periodic sampling and GCMS analysis of these samples. The conversion is usually complete within 6 hours. If only partially complete, additional ammonia is condensed into the cooled flask. After completion of the reaction, the mixture was warmed to room temperature and excess ammonia was evaporated off. Anhydrous sodium sulfate was added to the reaction mixture and the mixture was filtered through a plug of silica gel. The reaction flask was rinsed with 10mL of ethyl acetate and the solution was passed through the silica gel. The solvent was removed in vacuo to give a clear oil. Further purification was achieved by vacuum distillation.

Product 3- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (diethylamino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with diethylamine to provide menthyl glycinate 3 in 92% yield as a clear oil (boiling point about 160 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.73(d,3H,J＝7.0Hz),0.82-0.91(m,7H),0.92-1.2(m,1H),1.05(t,6H,J＝7.2Hz),1.31-1.40(m,1H),1.40-1.54(m,1H),1.60-1.73(m,2H),1.79-1.89(m,1H),1.94-2.04(m,1H),2.66(q,4H,J＝7.2Hz),3.30(s,2H),4.67-4.76(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,9.1,11.2,16.0,20.7,21.8,23.1,26.1,31.4,33.8,40.4,42.6,46.5,56.9,58.4,77.8,164.4. Low resolution MS (electron impact ionization): 269(M +),132,130,116,102.

Product 9- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (dipropylamino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with dipropylamine to provide menthyl glycinate 9 in 81% yield as a clear oil (boiling point at 1mm about 170 ℃).¹H NMR(300MHz,CDCl₃)δ,0.73(d,3H,J＝7.0Hz),0.80-0.89(m,13H),0.90-1.08(m,1H),1.30-1.51(m,6H),1.60-1.67(m,2H),1.79-1.88(m,1H),1.92-2.03(m,1H),2.48-2.55(m,4H),3.29(s,2H),4.65-4.74(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,11.7,16.2,20.6,20.7,22.0,23.3,26.2,31.3,34.2,40.9,46.9,55.2,56.3,74.1,171.1. Low scoreResolution MS (electron impact ionization): 297(M +),268,158,130,114,102.

Product 10- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (dibutylamino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with dibutylamine to provide menthyl glycinate 10 in 79% yield as a clear oil (boiling point about 180 ℃ at 1 mm). ¹H NMR(300MHz,CDCl₃)δ,0.72(d,3H,J＝7.0),0.83-0.90(m,13H),0.90-1.10(m,3H),1.19-1.53(m,9H),1.61-1.69(m,2H),1.76-1.90(m,1H),1.91-2.01(m,1H),2.54(t,4H,J＝7.2),3.27(s,2H),4.65-4.74(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,14.0,16.2,20.7,22.0,23.3,26.2,29.6,31.3,34.2,40.9,47.0,54.2,55.2,74.1,171.2. Low resolution MS (electron bombardment ionization): 325(M +),282,144,143,142,102,100.

Product 11- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (pyrrolidin-1-yl) acetate

Using the general procedure of 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with pyrrolidine to provide menthyl glycinate 11 in 81% yield as a clear oil (boiling point about 160 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.75(d,3H,J＝7.0),0.82-0.93(m,7H),0.95-1.11(m,2H),1.33-1.40(m,1H),1.41-1.56(m,1H),1.64-1.72(m,2H),1.76-1.92(m,5H),1.95-2.07(m,1H),2.60-2.70(m,4H),3.25-3.38(m,2H),4.71-4.80(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.3,20.7,22.0,23.4,23.8,26.3,31.4,34.2,40.9,46.9,53.9,57.1,74.3,170.4. Low resolution MS (electron impact ionization): 267(M +),224,130,128,100.

Product 5- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (piperidin-1-yl) acetate

Using the general procedure of 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with piperidine to provide menthyl glycinate 5 in 61% yield as a clear oil (boiling point about 180 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.70(d,3H,J＝4.2Hz),0.72-0.80(m,1H),0.84(d,3H,J＝3.6Hz),0.86(d,3H,J＝3.0Hz),0.87-1.0(m,3H),1.34-1.42(m,3H),1.54-1.65(m,6H),1.72-1.86(m,1H),1.90-1.96(m,1H),2.37-2.57(m,4H),3.07and 3.14(ABq,2H,J＝16.5Hz),4.61-4.75(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.3,20.7,22.0,23.4,26.3,31.4,34.2,41.0,42.2,46.9,53.9,58.2,74.6,170.0. Low resolution MS (electron impact ionization): 281(M +),266,144,142.

Product 12- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (cyclopropylamino) acetate

Using the general procedure for 1 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with cyclopropylamine to provide menthyl glycinate 12 in 74% yield as a clear oil (boiling point about 140 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.36-0.42(m,2H),0.42-0.48(m,2H),0.78(d,3H,J＝7.0Hz),0.85-0.90(m,6H),0.96-1.13(m,2H),1.34-1.44(m,1H),1.46-1.57(m,1H),1.67-1.73(m,2H),1.82-1.90(m,1H),1.97-2.04(m,1H),2.20-2.26(m,1H),2.40(bs,1H),3.34-3.42(m,2H),4.71-4.76(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,6.2,6.3,16.4,20.7,22.0,23.5,26.3,29.9,31.4,34.2,40.9,47.0,50.8,74.7,172.2. Low resolution MS (electron impact ionization): 253(M +),224,138,116,102.

Product 13- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (bis (2-methoxyethyl) amino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with bis (2-methoxyethyl) amine to provide menthyl glycinate 13 in 68% yield as a clear oil (boiling point about 200 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.69(d,3H,J＝7.0),0.75-0.86(m,7H),0.88-1.07(m,2H),1.25-1.35(m,1H),1.35-1.48(m,1H),1.54-1.66(m,2H),1.73-1.85(m,1H),1.87-1.96(m,1H),2.83-2.90(m,4H),3.24-3.28(m,6H),3.37-3.45(m,6H),4.59-4.71(m,1H)。

¹³C NMR(75MHz,CDCl₃) δ,16.2,20.7,22.0,23.3,26.2,31.3,34.2,41.0,46.9,53.9,55.9,58.7,71.4,74.1,171.1. Low resolution MS (electron impact ionization): 297(M +),284,190,160,146.

Product 14- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (isopentylamino) acetate

Using the general procedure for 1 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with isoamylamine to provide menthyl glycinate 14 in 90% yield as a clear oil (boiling point about 180 ℃ at 1 mm). ¹H NMR(300MHz,CDCl₃)δ,0.75(d,3H,J＝7.0Hz),0.87-0.92(m,13H),0.95-1.01(m,1H),1.03-1.13(m,1H),1.35-1.43(m,3H),1.43-1.59(m,1H),1.61-1.74(m,3H),1.77-1.89(m,1H),1.95-2.03(m,1H),2.10(s,1H),2.59-2.64(m,2H),3.38(s,2H),4.70-4.79(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.3,20.7,21.9,22.6,23.4,26.0,26.3,31.4,34.2,38.9,40.9,47.0,47.7,51.1,74.7,171.9. Low resolution MS (electron impact ionization): 283(M +),226,145,138,123,100.

Product 15- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (benzyl (methyl) amino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with N-methylbenzylamine to provide menthyl glycinate 15 in 90% yield as a clear oil (boiling point at 1mm about 210 ℃).¹H NMR(300MHz,CDCl₃)δ,0.78(d,3H,J＝7.0Hz),0.89(d,3H,J＝7.0Hz),0.91(d,3H,J＝7.0Hz),0.96-1.14(m,2H),1.34-1.43(m,1H),1.44-1.57(m,1H),1.64-1.72(m,2H),1.82-1.92(m,1H),1.99-2.05(m,1H),2.39(s,3H),3.24(s,2H),3.69(s,2H),4.73-4.82(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.3,20.7,22.0,23.4,26.3,31.4,34.2,41.0,47.0,57.7,74.2,127.1,128.2,129.1,138.4,170.5. Low resolution MS (electron impact ionization): 317(M +),180,178,135,134,120.

Product 7- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (isopropylamino) acetate

Using the general procedure for 1 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with isopropylamine to provide menthyl glycinate 7 in 88% yield as a clear oil (boiling point at 1mm ca. 140 ℃).¹H NMR(500MHz,CDCl₃)δ,0.75(d,3H,J＝7.0Hz),0.84-0.91(m,7H),0.92-1.0(m,1H),1.05(d,6H,J＝6.3Hz),1.34-1.40(m,1H),1.45-1.53(m,1H),1.64-1.69(m,2H),1.80-1.86(m,1H),1.96-2.00(m,1H),2.79(sep,1H,J＝6.2Hz),2.85(bs,1H),3.35-3.39(m,2H),4.70-4.76(m,1H)。¹³C NMR(125MHz,CDCl₃) δ,16.3,20.7,22.0,22.6,23.4,26.3,31.3,34.2,40.9,47.0,48.3,48.8,48.8,74.7,172.2. Low resolution MS (electron impact ionization): 255(M +),240,138,116,102.

Product 16- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (isopropyl (methyl) amino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with methyl-isopropylamine to provide menthyl glycinate 16 in 88% yield as a clear oil (boiling point about 160 ℃ at 1 mm).¹³C NMR(75MHz,CDCl₃) δ,16.2,18.4,18.4,20.7,22.0,23.4,26.3,31.3,34.2,38.3,40.9,46.9,53.4,55.1,74.3,171.0. Low resolution MS (electron bombardment ionization): 269(M +),254,138,132,130,116.

Product 6- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (diisobutylamino) acetate

Using the general procedure for 2 ° amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with diisobutylamine to provide menthyl glycinate 6 in 86% yield as a clear oil (boiling point about 180 ℃ at 1 mm).¹H NMR(300MHz,CDCl₃)δ,0.74(d,3H,J＝7.0),0.82-0.91(m,19H),0.92-1.11(m,2H),1.30-1.38(m,1H),1.40-1.54(m,1H),1.60-1.71(m,4H),1.81-1.91(m,1H),1.94-2.01(m,1H),2.31(d,4H,J＝7.3),3.26(s,2H),4.65-4.74(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.2,20.6,20.7,22.0,23.3,26.2,26.7,31.4,34.2,41.0,47.0,56.0,63.4,73.9,171.6. Low resolution MS (electron impact ionization): 325(M +),283,282,144,142,100.

Product 17- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (tert-butylamino) acetate

Using the general procedure with 1 ℃ amine, (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2) was reacted with tert-butylamine to provide menthyl glycinate 17 in 78% yield as a clear oil (at 1 m) m has a boiling point of about 180 deg.c).¹H NMR(300MHz,CDCl₃)δ,0.73(d,3H,J＝7.0Hz),0.86-0.90(m,7H),0.90-1.04(m,1H),1.09(s,9H),1.29-1.37(m,1H),1.38-1.54(m,1H),1.57-1.72(m,3H),1.79-1.92(m,1H),1.94-2.07(m,1H),3.35(s,2H),4.68-4.77(m,1H)。¹³C NMR(75MHz,CDCl₃) δ,16.3,20.7,21.9,23.4,26.2,28.7,31.3,34.2,40.8,44.9,47.0,50.2,74.6,172.7. Low resolution MS (electron impact ionization): 269(M +),254,130,116.

Product 18- (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2- (methyl (pyridin-2-yl) ethyl) amino) acetate

(1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 1.3g, 4.69mmol) was dissolved in 25mL EtOAc, and NaOH (1.2g, 0.03mol) and anhydrous Na were added to the solution₂SO₄(0.5 g). 2- (2-methylaminoethyl) pyridine (1.0mL, 7.22mmol) was added to the solution, and the mixture was stirred at room temperature for 4 hours or until GC-FID analysis showed no remaining bromo ester 2. The solution was then filtered through glass wool and the solvent was removed under reduced pressure. The resulting oil was subjected to vacuum distillation (at 1mm, 120 ℃ for 2h) to remove excess 2- (2-methylaminoethyl) pyridine. The residual oil was added to 20mL EtOAc and passed through SiO₂And (6) a plug. After removal of the solvent, an oil was obtained which was predominantly menthyl glycinate 18(1.54g, 4.63mmol, 99%). The product was further refined by distillation (boiling point at 1mm of about 230 ℃) to provide pure menthyl glycinate 18 in 75% yield as a clear oil: ( ¹H NMR(300MHz,CDCl₃)δ,0.73(d,3H,J＝7.0Hz),0.80-0.92(m,7H),0.89-1.10(m,2H),1.31-1.43(m,1H),1.43-1.54(m,1H),1.61-1.70(m,2H),1.77-1.89(m,1H),1.94-2.05(m,1H),2.44(s,3H),2.89-3.01(m,4H),3.29(s,2H),4.69-4.78(m,1H),7.06-7.11(m,1H),7.18(d,1H,J＝7.8Hz),7.54-7.60(m,1H),8.49-8.51(m,1H))。¹³C NMR(75MHz,CDCl₃)δ,16.2,20.7,22.0,23.4,26.3,31.4,34.2,36.3,41.0,46.9,56.8,58.7,74.4,121.1,123.1,136.3,149.2,160.2,170.5。

The product, 20-bis ((1R,2S,5R) -2-isopropyl-5-methylcyclohexyl) 2,2' - (isopropylimino) diacetate

(1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 2.33g, 8.4mmol) was dissolved in 25mL EtOAc, and NaOH (1.2g, 0.03mol) and anhydrous Na were added to the solution₂SO₄(0.5 g). Isopropylamine (0.25mL, 2.9mmol) was added to the solution and the mixture was stirred at room temperature for 5 hours or until GC-FID analysis showed no remaining bromo ester 2. The solution was then filtered through glass wool and the solvent was removed under reduced pressure. The resulting oil was subjected to vacuum distillation (at 1mm, 160 ℃ for 20min) to remove excess bromo ester 2. The distillate was a clear oil (about 0.5g), which was identified as a mixture of bromo ester 2 and desired product 20. The residual oil was added to 20mL EtOAc and passed through SiO₂And (6) a plug. After removal of the solvent, a clear oil was obtained as menthyl glycinate 20(0.425g, 0.94mmol, 32%).¹H NMR(300MHz,CDCl₃)δ,0.76(d,6H,J＝6.9Hz),0.85-0.95(m,14H),0.94-1.04(m,2H),1.04-1.10(m,4H),1.33-1.42(m,2H),1.42-1.55(m,2h),1.64-1.73(m,4H),1.80-1.93(m,2H),1.96-2.04(m,2H),3.04-3.13(sep,1H,J＝6.5Hz),3.54(s,4H),4.68-4.77(m,2H)。¹³C NMR(75MHz,CDCl₃)δ,16.3,20.3,20.7,22.0,23.4,26.3,31.4,34.3,40.9,47.0,52.7,74.2,171.8。

The product, 21-bis ((1R,2S,5R) -2-isopropyl-5-methylcyclohexyl) 2,2' - (ethane-1, 2-diylbis (methylimino)) diacetate

(1R,2S,5R) -2-isopropyl-5-methylcyclohexyl 2-bromoacetate (2, 2.13g, 7.7mmol) was dissolved in 50mL EtOAc, and NaOH (1.2g, 0.03mol) and anhydrous Na were added to the solution ₂SO₄(0.5 g). N, N-dimethylethylenediamine (0.3mL, 2.79mmol) was added to the solution, and the mixture was stirred at room temperature for 5 hours or until GC-FID analysis showed no remaining bromo ester 2. The solution was then filtered through glass wool and the solvent was removed under reduced pressure. The resulting oil was subjected to vacuum distillation (at 1mm, 170 ℃ C. and 190 ℃ C. for 30min) to remove excess bromo ester 2. The residual yellow oil was added to 20mL EtOAc and passed through SiO₂And (6) a plug. After removal of the solvent, a clear oil was obtained as menthyl glycinate 21(0.84g, 1.75mmol, 43%).¹H NMR(500MHz,CDCl₃)δ,0.78(d,6H,J＝6.7Hz),0.82-0.95(m,14H),0.96-1.13(m,4H),1.37-1.42(m,2H),1.43-1.55(bs,2H),1.70(d,4H,J＝2.4Hz),1.80-1.90(m,2H),2.00(d,2H,J＝6.9Hz),2.48(s,6H),2.82(s,4H),3.42(s,4H),4.74-4.78(m,2H)。¹³C NMR(125MHz,CDCl₃)δ,16.3,20.7,22.0,23.4,26.3,31.4,34.2,41.0,42.2,46.9,53.9,58.2,74.6,170.0。

Example 1: toxicology review of menthol derivatives

The recommended "sipand spit" concentrations of the compounds indicated by the product numbers used in table 1 were examined and the preliminary safety was evaluated. The products 3, 5-7, 9-11, 13, 15, 16, 18 and (1R,2S,5R) -2-isopropyl-5-methylcyclohexyl-2- (dibenzylamino) acetate were investigated. These compounds and potential decomposition compounds were investigated using a toxicological predictive database. It was determined that samples containing 100ppm of menthol derivatives could be safely tested using the "spit-up" method.

Example 2: preliminary sensory evaluation

Solutions were prepared for sensory testing using the "spit method" method. A100 ppm menthol derivative solution was prepared by adding 0.025g of the menthol derivative and the appropriate amount (Q.S.) of deionized water (DI) at 20 ℃ in a 250mL volumetric flask. The solution was dispersed by stirring before tasting. A panel of six participants tasted. The compounds evaluated were: XI-1-48 (product 9), DK-1-36 (product 5), XI-1-50 (product 16), DK-1-34 (product 6), RK-1-10 (product 15), DK-2-44 (product 11), RK-2-10 (product 10), DK-1-44 (product 13), dimethylaminoglycinate (product 4) and RK-2-10 (product 7). The taste results reveal the unique properties of this class of compounds. Overall, 100ppm of material showed a delayed onset of cooling sensation between 20 seconds and 40 seconds. These compounds exhibit very different cooling episodes than menthol, which provides an immediate cooling sensation.

The organoleptic properties of the menthol derivatives in water are listed below according to the compounds:

XI-1-48 (product 9): slight ester/fruit notes with a cooling sensation of latent onset.

DK-1-36 (product 5): the compound has no cool feeling.

XI-1-50 (product 16): has no peculiar smell, and has cold feeling attack in 20 seconds and strong cold feeling in 1 minute.

DK-1-34 (product 6): sweet metal taste, no pungent taste, and a cool feeling after 20 seconds.

RK-1-10 (product 15): dry mouthfeel, very slight cooling sensation, but delayed onset after 30 seconds.

DK-2-44 (product 11): smelling like chlorine with the taste of swimming pool water.

RK-2-10 (product 10): delay onset cooling for more than 20 seconds; the very strong cool feeling curve extends to after two minutes.

DK-1-44 (product 13): bitter, numb tongue, slight cool sensation, and even cooler after continuous washing with water.

Product 4: mint-like cool, very light, early cool.

DK-2-39 (product 7): the cool feeling is delayed significantly for more than 30 seconds, and the cool feeling lasts for a long time until 2 minutes later.

Example 3: sensory evaluation of menthol derivatives in ethanol (EtOH), Propylene Glycol (PG) and water.

Stock solutions of each solution were prepared to a final concentration of 100ppm as described below.

Prepared from an aqueous solution containing ethanol:

stock solutions

a. A stock solution of 2.5% ethanol solution was prepared by adding 25mg menthol analog to 1 gram of ethanol (thoroughly mixed).

b. An appropriate amount (Q.S.) of deionized water was added to a total weight of 250 grams.

C. Mix well to achieve a final concentration of 100 ppm.

Preparation with aqueous PG-containing solution:

Stock solutions

a. Stock solutions of 2.5% PG solutions were prepared by adding 25mg menthol analog to 1 gram of PG (thoroughly mixed).

c. Mix well to achieve a final concentration of 100 ppm.

Preparation with water:

stock solutions

a. 25mg of menthol derivative and an appropriate amount (Q.S.) of deionized water were added to a total weight of 250 grams to achieve a final concentration of 100 ppm.

The organoleptic properties of the menthol derivatives in ethanol, propylene glycol and water are listed below:

RK-2-10 (product 10) exhibited a cool sensation with delayed onset and a bitter early-phase from PG.

XI-1-60 (product 7) samples exhibited a late cooling after about 10 seconds and a very intense cooling environment at about 40 seconds.

XI-1-50 (product 16) delayed the cooling after 20 seconds with some of the early bitterness from PG. A very strong cooling sensation was produced after 50 seconds.

XI-1-50 (product 16) PG: the initial bitterness from PG, was cool over 30 seconds and persisted until after 1.5 minutes.

XI-1-50 (product 16) EtOH: the initial alcohol cooling, burning sensation, was late at 20 seconds and deep at 60 seconds.

XI-1-60 (product 7) PG: the cooling sensation at the early stage of 10 seconds, the cooling sensation stronger at 20 seconds, and the cooling sensation much stronger than XI-1-50.

XI-1-60 (product 7) EtOH: the cooling curve starts at 20 seconds and is very strong from 20 seconds to 2 minutes with a slight alcohol burning.

RK-2-10 (product 10) PG: a very low intensity cooling sensation was slowly produced, with a skin tingling sensation. Use within taste thresholds may be good candidates for taste improvement applications and bitter taste masking.

RK-2-10 (product 10) EtOH: delayed onset of a mild cooling sensation (after 20 seconds), with a slight tingling sensation and sweetness lasting for more than 1 minute.

The sensory properties of menthol in simple solutions of PG and water or ethanol were evaluated and it was found that menthol provides a very strong instant cooling effect.

Example 4: study of hydrolysis

The hydrolysis of menthol derivatives (also known as menthol analogues) over time was evaluated using Gas Chromatography (GC). The mean area ratio of menthol analogue and menthol (area of target component divided by area of internal standard) was measured initially, after 24 hours, after 48 hours, after 1 week and after 2 weeks.

Stock solutions of each menthol derivative in ethanol, PG or water were prepared as described below to a final concentration of 200 ppm. 5mL of 200ppm stock solution was mixed with 1mL of Internal Standard (IS) and added to 10.00mL of chloroform. The organic layers were transferred to respective GC vials and run. The run was repeated for each GC. All stock solutions were stored at room temperature in the dark. All stock solutions were stored at room temperature in the dark.

Prepared from an aqueous solution containing ethanol:

stock solutions

a. Stock solutions of 5% ethanol solution were prepared by adding 50mg menthol analog to 1 gram of ethanol (mixed well).

c. Mix well to achieve a final concentration of 200 ppm.

Preparation with an aqueous solution containing propylene glycol:

stock solutions

a. Stock solutions of 5% PG solution were prepared by adding 50mg menthol analogue to 1 gram of PG (thoroughly mixed).

c. Mix well to achieve a final concentration of 200 ppm.

Preparation in water:

stock solutions

a. Stock solutions of 5% solutions were prepared by adding 50mg menthol analogue to deionized water.

c. Mix well to achieve a final concentration of 200 ppm.

Figures 1-9 graphically illustrate the average area ratio of menthol analog and menthol over different time periods. As the menthol analog is hydrolyzed, more menthol is present in the solution. Figure 10 illustrates the average area ratio of menthol in ethanol.

Example 5: solubility analysis

Hansen Solubility Parameters of menthol derivatives were calculated using Hansen Solubility Parameters In Practice (HSPiP). The use authorization is given to: the HSPiP version 5 5.1.02 of the Fona International (FONA International) was calculated. Table 3, shown below, lists data for various menthol derivatives and target solvents from hansen solubility parameters.

Table 3: hansen solubility parameter

Example 7: electronic tongue test example (predictive)

The target compounds were tested using an instrument called an electronic tongue for measuring and analyzing flavor characteristics. The target compound is tested and the results compared to known cooling agents. The electronic tongue has seven sensors that can detect the same dissolved organic and inorganic compounds as human taste receptors. Like the human receptors, each sensor has a series of different responses. The information provided by each sensor is complementary and the combination of the results from all sensors produces a unique fingerprint for the compound being analyzed.

Example 8: measuring the time-intensity of menthol and menthyl glycinate in lozenges, beverage model systems and mouthwashes

In this example, the experimental compound names correspond to the products shown in table 1. RK-2-10 corresponds to product 10 in Table 1. DK-1-50 corresponds to product 16 in Table 1. XI-1-60 corresponds to product 7 in Table 1. XI-1-65 corresponds to product 12 in Table 1. XI-2-73 corresponds to product 15 in Table 1.

To evaluate the potential use of menthyl glycinate as a sensate in different food, beverage and oral hygiene products, selected compounds were incorporated into different application systems. Beverage model systems, lozenge and mouthwash applications were created and time-intensity analyses were performed using trained discriminant analysis panelists.

Time-intensity (TI) is a time-sensitive method. In the TI assessment process, the assessor is asked to score the perceived intensity of a single attribute of product use. TI analysis can characterize the onset, decay, and rate of a particular sensory feature, as compared to a single point measurement. This analysis can represent rich information on the intensity of an attribute in the time domain and identify temporally perceived differences between samples that can greatly affect the overall characteristics of the product. For each sample evaluation, a time curve was generated based on the repeat case. The time profiles for each panelist were combined to generate a combination profile for each product evaluated. The following different parameters were calculated:

I_max: peak intensity or maximum observed intensity over the entire curve;

T_start: the time point on the curve at which the response to the stimulus is first perceived;

T_max: the time location of the peak intensity on the curve;

T_plateau: an extension of the maximum intensity or a duration of the maximum intensity;

T_ext: the point in time of the perceived disappearance of the stimulus, defined as the time position of the disappearance of the intensity measured after the peak intensity (or the end of the evaluation window);

I_ext: intensity at disappearance or at end of assessment;

R_increase：T_startand T_maxThe slope or rate of increase in intensity;

R_decrease：T_startAnd T_maxThe slope or rate of decrease in intensity; and

area (Area): total area under the time-intensity curve.

Details and results regarding the evaluation of selected menthyl glycinate esters in use are shown below.

Lozenge applications

Lozenge applications were created using the formulations detailed in table 4 to evaluate the target menthyl glycinate esters using time-intensity analysis.

TABLE 4 lozenge formulation, 100g of raw materials per batch

The following test compounds were evaluated: RK-2-10, menthol, DK-1-50, XI-1-60 and XI-1-65.

Sensory evaluation of lozenge applications

Time-intensity (T-I) evaluation of the cooling intensity of the lozenges, 9 panelists (3 males, 6 females) were recruited. Panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) is provided for use as a cross-modal reference to help assess the intensity of the cooling attributes present in the lozenge sample. Panelists evaluated samples in parallel twice, all samples were blind and presented in random order using a 3 digit code. Panelists were instructed to provide cooling intensity at predetermined time points throughout the 4 minute evaluation window. The samples were pre-weighed (2g) and the panelists were instructed to evaluate the full amount of the samples to ensure consistency between panelists and repeat evaluations. There is at least a 4 hour interval between evaluations to ensure there is no carry over (carry over).

Data analysis for generating T-I statistics and ANOVA analysis for determining significant differences between samples were performed using R STUDIO.

Results of lozenge application

All relevant T-I parameters for the troches are shown in table 5. Maximum Cool Strength (I) of all samples_max) The values indicate that all test compounds evaluated have a strong cooling potential (cooling range of about 9-11.5). The analysis by ANOVA showed that,the maximum cooling intensity of the menthyl glycinates XI-1-60 and XI-1-65 is not significantly different from that of menthol, which supports the strong cooling potential. Although the maximum cooling intensity of the menthyl glycinates RK-2-10 and DK-1-50 was significantly different from that of menthol as a whole, their cooling potential was still strong according to panelist ratings. For some of the samples evaluated, T was found_startThere was a significant difference indicating that there was a significant difference in the time curve and the onset of cooling. More specifically, the menthyl glycinates RK-2-10 and DK-1-50 exhibited significantly delayed onset of cooling compared to menthol. Onset of menthyl glycinate XI-1-65 is almost identical to menthol. XI-1-60 exhibited a delayed onset trend, but did not differ significantly from menthol. Although not all menthyl glycinate exhibited significant differences in onset of cooling compared to menthol, all menthyl glycinate tested had a significant delay in T compared to menthol _max. This shows a significantly different cool time profile. The rate of increase and decrease in cooling intensity also indicates a significant difference between menthol and menthyl glycinate. All menthyl glycinate esters tended to be lower than menthol, with RK-2-10 and DK-1-50 having significantly lower rates of increase and decrease, and XI-1-60 having significantly lower rates of decrease, indicating that a longer lasting cooling sensation was possible.

Fig. 11 illustrates a time-intensity graph of cooling sensation. The total area under the T-I curve (AUC) was also analyzed, which correlates to the total perceived cooling intensity over the evaluation time window. Glycine menthyl esters XI-1-60 and XI-1-65 do not differ significantly from menthol, whereas RK-2-10 and DK-1-50 are significantly lower.

Overall, the menthyl glycinate esters in lozenges exhibit interesting time profiles, which suggests their potential use in sensory blends to achieve a more long-lasting/lasting cooling effect. Hybrid customization can lead to optimized products due to lower cool add and drop rates and strong cool potential.

TABLE 5 time-intensity analysis statistics. Results were obtained by evaluation of the troches by 9 trained panelists. Lozenges containing the following cool test compounds were evaluated: RK-2-10, menthol, DK-1-50, XI-1-60 and XI-1-65. Each sample was evaluated in parallel twice within a time window of 4 minutes.

I_max

T_start

T_max

R_Inc

R_Dec

AUC

RK-2-10

9.06^a

8.74^a

210.00^a

0.038^ac

0.038^a

1669.06^a

Menthol

11.53^bc

5.00^b

180.00^b

0.053^b

0.056^b

2064.83^b

DK-1-50

9.41^a

7.85^ac

204.71^a

0.039^ac

0.032^a

1698.24^a

XI-1-60

9.88^ac

6.55^bc

210.00^a

0.041^ab

0.021^c

1750.31^ab

XI-1-65

10.31^c

5.31^b

206.25^a

0.042^ab

1945.31^bc

The different superscript letters in each column represent statistical significance (ANOVA α ═ 0.5, p < 0.05). For variables with the same letter, the difference is not statistically significant. Furthermore, for variables with different letters, the difference has statistical significance.

Beverage model system

A simple beverage model system was created using the detailed formula in table 6 to evaluate the target menthyl glycinate esters using time-intensity analysis.

TABLE 6 beverage model System formulation, 100g raw materials per batch

Raw materials	Quantity (g)
		Water (W)	97.99
Propylene glycol	2
		Test compounds	0.01

The following test compounds were evaluated: RK-2-10, menthol, DK-1-50 and XI-1-60.

Sensory evaluation of beverage model systems

For time-intensity (T-I) evaluation of the cooling attributes of the model beverage system, 8 panelists (2 males, 6 females) were recruited. Panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) is provided for use as a cross-modal reference to help assess the intensity of the cooling attribute (cool attribute) present in the model beverage sample. Panelists evaluated samples in parallel twice, all samples were blind and presented in random order using a 3 digit code. The panelists were instructed to hold the samples in the mouth for 30 seconds and then expectorate. During the hold period, panelists were instructed to notice the onset and intensity of cooling. After expectoration, panelists continued to report cool intensity at the predetermined time point throughout the 2 minute evaluation window. The samples were pre-weighed and panelists were instructed to evaluate the full amount of the sample to ensure consistency between panelists and repeat evaluations. At least 4 hours were left between evaluations to ensure no carryover.

Results of beverage model System

All relevant T-I parameters for the beverage model system are shown in table 7. Maximum Cool Strength (I) of all samples_max) The values show that all test compounds evaluated have a strong cooling potential, especially in view of the low level of incorporation (100ppm) in the model beverage system. ANOVA analysis showed that the maximum cooling intensity of menthyl glycinate XI-1-60 was not significantly different from that of menthol, supporting the strong cooling potential of this compound. Overall, while the peak intensity of cooling for the menthyl glycinates RK-2-10 and DK-1-50 was significantly different from that of menthol, their cooling potential was still strong according to the panelist's score. T was found for menthol and all menthyl glycinate esters_startThe significant difference indicates that there was a significant difference in the time profile and onset of cooling for all the new compounds evaluated compared to menthol. The time to maximum cool intensity was also evaluated, and while all menthyl glycinate exhibited a higher tendency to peak onset compared to menthol, only the DK-1-50 differed significantly. This observed trend further supports the ability of these menthyl glycinates to bring about different time profiles. This evaluation also additionally examined the plateau time, which is significantly higher for menthyl glycinates RK-2-10 and XI-1-60 than menthol, although menthol is not significantly different from DK-1-50, indicating the potential to retain the peak intensity longer. The rate of increase in cooling intensity also indicates a significant difference between menthol and menthyl glycinate. Hair-like device All menthyl glycinate now has a significantly lower rate than menthol, indicating a more durable and sustained cooling sensation is possible.

Fig. 12 illustrates a time-intensity plot of cooling effect in a beverage model system. The total area under the T-I curve was also analyzed, which correlates to the total perceived cooling intensity within the evaluation time window. Menthol glycinate XI-1-60 did not differ significantly from menthol, whereas RK-2-10 and DK-1-50 were significantly lower.

Overall, the menthyl glycinate esters in the beverage model system exhibited interesting time profiles, which suggests their potential use in sensory blends to achieve a more long-lasting/sustained cooling effect. With a lower rate of cool enhancement, longer cool onset times, time to maximum intensity, and strong cool potential, mix customization can lead to optimized beverage products.

TABLE 7 time-intensity analysis statistics. Results were obtained by evaluation of the beverage model system by 9 trained panelists. Beverage systems were tested using the following cool test compounds: RK-2-10, menthol, DK-1-50, XI-1-60 were evaluated. Each sample was evaluated in parallel twice within a 2 minute time window.

I_max

T_start

T_max

T_plateau

R_Inc

R_Dec

AUC

Menthol

5^a

10^a

50.2^a

23.3^a

0.12^a

0.03^a

429.1^a

RK-2-10

2.5^b

6.1^b

58.9^ab

39.6^b

0.04^b

0.06^a

260.1^b

DK-1-50

3.7^b

16^c

71.6^b

21.8^a

0.05^b

0.02^a

319.6^bc

XI-1-60

4.2^ab

16^c

60.5^ab

37.2^b

0.06^b

0.02^a

355^ac

The different superscript letters in each column represent statistical significance (ANOVA α ═ 0.5, p < 0.05).

Mouthwash application

The formulation shown in table 8 was employed to create a mouthwash product to evaluate the target menthyl glycinate using a time-intensity analysis.

Table 8: mouthwash application formula

The following test compounds were evaluated: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50 and XI-2-73.

Sensory evaluation of mouthwash applications

Time-intensity (T-I) evaluation of cooling attributes of mouthwash products, 8 panelists (2 males, 6 females) were recruited. Panelists were trained in basic taste descriptive analysis. A sweetness reference series (intensity range 2-12) is provided for use as a cross-modal reference to help assess the intensity of the cooling attributes present in the mouthwash sample. Panelists evaluated samples in parallel twice, all blinded and using a 3-digit code to evaluateAnd presenting in a random order. Panelists evaluated 15ml of mouthwash at once and were instructed to rinse for 30 seconds before spitting. Panelists were instructed to provide cooling intensity before and after expectoration. For the time before spitting, the evaluation was started at the time of pouring the sample, and thereafter, the evaluation was performed every 10 seconds. After expectoration, the assessment lasted 15 minutes and the panelists provided a cool intensity rating at the predetermined time. Due to the unique properties of the product and the interest in extending the length of time of the cooling attributes after consumption, an additional parameter I was evaluated in the samples by ANOVA _ext. This parameter is the intensity of the cooling sensation at the time of disappearance of the cooling sensation, or in our case the intensity of the cooling sensation at the end of the evaluation.

Results of mouthwash application

All relevant T-I parameters for mouthwash applications are given in tables 9a, 9b and 10. Maximum Cool Strength (I) of all samples_max) The values indicate that all the glycine menthyl ester compounds evaluated have a strong cooling potential.

The time intensity analysis data (Table 9a) of the mouthwash samples evaluated during the 30 second rinse phase show that all the new glycinates had a maximum cool feel intensity similar to menthol, with higher trends for glycinates XI-I-65, DK-1-50 and XI-2-73, but with no statistical significance. Initial sensing time (T) between samples during this washing phase_start) Time maximum intensity (T)_max) And the total area under the curve also did not differ significantly, further supporting the cooling potential of the new glycine ester in view of the general use of menthol in oral hygiene applications. R decrease (T) between menthol and menthyl glycinate_maxAnd T_extThe slope or rate of intensity drop therebetween) show significant differences. The R decay of menthyl glycinate esters XI-I-60, RK-2-10, XI-I-65, DK-1-50 and XI-2-73 is significantly lower and somewhat close to zero. This indicates that all menthyl glycinate retained its maximum cooling intensity throughout the flush period, while menthol began to decline before expectoration.

The time intensity analysis (table 9b) used to evaluate the cooling potential of neoglycine menthol ester in mouthwash applications after expectoration indicates that all of the neoglycine esters had a similar maximum cooling intensity as menthol, and all of the glycine esters tended to be higher compared to menthol. Despite the initial sensing time (T) in the tested compounds_start) And time maximum intensity (T)_max) There was no significant difference, but an interesting difference in the values of R incrase and R decrease was observed. R incrasose (T) of menthyl glycinates XI-I-65, RK-2-10 and XI-2-73 compared to menthol_startAnd T_maxThe slope or rate of increase in intensity therebetween) is positive and significantly higher than menthol, indicating that the cool intensity continues to rise even after expectoration, while the same trend is not observed for menthol. This suggests that these glycinates have great cooling potential and the ability to influence the temporal cooling profile in mouthwash applications. In addition, R decrease (T) of menthol glycinate compared to menthol_maxAnd T_extThe slope or rate of the intensity drop therebetween) is significantly lower, indicating that menthyl glycinate is able to maintain a more intense and longer lasting cooling sensation after the rinse phase. Figure 13 illustrates a time-intensity graph of the cooling sensation of mouthwash. The total area under the T-I curve also indicates a higher trend for all menthyl glycinates when compared to menthol, with a significantly higher DK-1-50.

Due to the unique properties of mouthwash products and the interest in prolonging the cooling attributes after expectoration, I_extAn evaluation was performed to compare the intensity of the cooling sensation at the time of disappearance of the cooling sensation or at the end of the evaluation in our case. The results (Table 10) show that menthyl glycinates XI-1-65 and DK-1-50 have significantly higher cool feel strengths at the end of our evaluation window when compared to menthol. This observation further supports the potential of these new sensates to extend the cooling attributes in oral hygiene applications. Unique mixtures of these compounds have the potential to further alter the time profile of the cooling attributes and therefore have great potential in a variety of flavor applications.

Tables 9a-9 b: time-intensity analysis statistics. Results were obtained by 8 trained panelists evaluating the mouthwash products. Mouthwash products included the following cooling test compounds: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50 and XI-2-73. Each sample was evaluated in parallel twice in 2 different time windows: the rinsing phase lasted 30 seconds (table 9a) and 15 minutes after spitting (table 9 b).

TABLE 9a

Product of

I_max

T_start

T_max

R_inc

R_dec

AUC

Menthol

12.56^a

10.88^a

16.18^a

0.21^a

-0.09^a

168.97^a

XI-I-60

12.43^a

11.00^a

16.33^a

0.20^a

-0.02^b

170.50^a

RK-2-10

12.82^a

10.91^a

15.00^a

0.18^b

-0.01^b

182.05^a

XI-I-65

13.50^a

10.00^a

17.08^a

0.23^a

0.00^b

186.88^a

DK-1-50

13.09^a

10.00^a

17.27^a

0.23^a

0.00^b

180.91^a

XI-2-73

13.00^a

10.00^a

17.50^a

0.21^a

0.00^b

179.79^a

TABLE 9b

Product of

I_max

T_start

T_max

R_inc

R_dec

AUC

Menthol

12.01^a

30.00^a

33.53^a

0.00^a

-0.03^a

3608.38^a

XI-I-60

12.33^ab

30.00^a

36.00^a

0.00^a

-0.01^b

4344.50^ac

RK-2-10

12.65^ab

30.00^a

0.00^a

-0.01^b

4105.91^ac

XI-I-65

13.20^ab

30.00^a

32.50^a

0.03^b

-0.01^b

5211.25^bc

DK-1-50

13.37^ab

30.00^a

32.73^a

0.03^b

-0.01^b

5565.00^b

XI-2-73

13.50^ab

30.00^a

32.50^a

0.03^b

-0.01^b

4082.50^ac

TABLE 10 Cool feeling vanishment or evaluation of cool feeling intensity at the end. The mouthwash product evaluated the following cool test compounds: menthol, XI-I-60, RK-2-10, XI-I-65, DK-1-50 and XI-2-73. Each sample was evaluated in parallel, with the parameter emphasis on the cool intensity reported 15 minutes after expectoration.

Product of	I_ext
		Menthol	1^a
XI-I-60	1.23^a
		RK-2-10	0.9^a
XI-I-65	2.18^b
		DK-1-50	2.33^b
XI-2-73	0.67^a

Reference to the literature

(1)Eccles,R.(1994).“Menthol and Related Cooling Compounds".J.Pharm.Pharmacol.46(8):618–630.

(2)“Update on Menthol Production&Use.”http://www.leffingwell.com/menthol1/menthol1.htm；downloaded 12/31/18.

(3)“Cool without Menthol&Cooler than Menthol and Cooling Compounds as Insect Repellents.”Leffingwell,J.C.,http://www.leffingwell.com/cooler_than_menthol.htm；12/31/18.

(4)“Common Fragrance and Flavor Materials:Preparation,Properties and Uses 4th Ed.”Bauer,K.；Garbe,D.；Surburg,H.,Wiley-VHC,Weinheim,Germany,2001.

(5)Hettstedt,C.；Betzl,W.；Karaghiosoff,K.Zeits.Anorg.Allgem.Chemie 2012,638,377.For alternative routes leading to compound 2,see:

(6)Shankar,S.P.；Jagodzinska,M.；Malpezzi,L.；Lazzari,P.；Manca,I.；Greig,I.R.；Sani,M.；Zanda,M.Org.Biomol.Chem.2013,11,2273.

(7)Singh,R.；Ghosh,S.K.Tetrahedron:Asymmetry,2014,25,57.d.Streinz,L.；Koutek,B.；Saman,D.Synlett,2001,809.

(8)Dentel,H.；Chataigner,I.；Lohier,J.-F.；Gulea,M.Tetrahedron,2012,68,2326.

(9)Yin,Y.；Wu,M.；Zubcevic,L.；Borschel,W.F.；Lander,G.C.；Lee,S.-Y.Science,2018,359,237.

(10)Shirai,T.；Kumihashi,K.；Sakasai,M.Kusuoku,H.；Shibuya,Y.；Ohuchi,A.ACS Med.Chem.Lett.2017,8,715.

(11)Kweka,E.J.,et al.,Protective efficacy of menthol propylene glycol carbonate compared to N,N-diethyl-methylbenzamide against mosquito bites in Northern Tanzania,Parasites&Vectors,5:189(2012)

(12)Hansen Solubility Parameters in Practice,available at https:// www.hansen-solubility.com/HSPiP/.

(13)“Synthesis of Menthol Glycinates and Their Potential as Cooling Agents.”Klumpp,D.A.；Sobel,R.M.；Osei-Badu,B.；Liveras,Z.；Klumpp,R.A.；Kokkinidou,S.G.；Stentzel,M.R.ACS Omega,2020,5,4043-4049(doi.org/10.1021/acsomega.9b03624).

Claims

1. A compound of formula (I):

wherein R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring,

R₁and R₂Each containing up to 20 carbon atoms, and

with the proviso that the compound is not N, N-dimethylglycin menthyl ester, N-diethylglycin menthyl ester or N, N-dihydroxyethylglycin menthyl ester.

2. A method of providing a cooling sensation in an oral cavity comprising: an orally administered cooling agent, wherein the cooling agent is a compound of formula (I):

R₁and R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, an

R₁And R₂Each containing up to 20 carbon atoms.

3. An insect repellent comprising: a compound of the formula (I),

and a solvent or a carrier,

wherein R is₁And R₂Independently selected from: H. alkyl and R₁And R₂Together with the N atom to which they are attached form a 4 to 8 membered ring, an

R₁And R₂Each containing up to 20 carbon atoms.

4. An oral hygiene product or an edible product comprising: a compound of formula (I)

And a solvent or a carrier, wherein,

R₁And R₂Each containing up to 20 carbon atoms.

5. A compound of formula (II):

or a compound of formula (III):

R₁and R₂Each containing up to 20 carbon atoms, and

l is alkylene, arylene, - (CH)₂)_X-(OCH₂CH₂)_nO-(CH₂)_X-, where x and n are independently 1 to 10 and x + n is at most 10,

or

Wherein R is₁And R₂Each independently selected from H and OH, and a and b are independently 0, 1, 2 or 3, wherein the L group has up to 20 carbon atoms.

6. A method of making menthyl glycinate, comprising:

Reacting menthol with bromoacetyl bromide or chloroacetyl chloride to form an ester,

separating off the ester, and

reacting the ester and amine to form the menthyl glycinate ester.

7. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁And R₂At least one of which is a substituted alkyl group.

8. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein the substituted alkyl group is a group comprising a member selected from: aryl groups, ether groups and amine groups.

9. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁And R₂At least one of which is an alkyl group of 3 to 6 carbon atoms.

10. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁And R₂At least one of which is a propyl group.

11. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁Selected from: a methyl group, an ethyl group and a hydrogen atom.

12. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁Comprising at least one group selected from: piperidine and pyridine.

13. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁And R₂And the N atom to which they are attached form a piperidine ring or a pyrrolidine ring.

14. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein R₁And R₂Alkyl groups containing from 3 to 6 carbon atoms.

15. A compound, insect repellent, product or method as claimed in any one of the preceding claims, wherein the cooling agent is provided in a form selected from: candies, gums, beverages, mouthwashes and toothpastes.

16. A method of repelling insects comprising: administering a compound, product or insect repellent according to any one of the preceding claims.

17. A skin cream or shaving gel comprising: a compound or product according to any preceding claim, and a carrier.

18. The method of any one of the preceding claims, wherein the menthol is reacted with the bromoacetyl bromide.

19. A compound, insect repellent, product or method as claimed in any one of the preceding claims wherein L is selected from methylene, (CH)₂)₂、(CH₂)₃、(CH₂)₄、(CH₂)(CH)(CH₃) And (CH)₂)(CH₂)(CH)(CH₃)。

20. A method of providing a cooling sensation in an oral cavity comprising: an oral cooling agent, wherein the cooling agent is a compound or product of any of the preceding claims.

21. An insect repellent comprising: a compound, product or insect repellent according to any preceding claim, and a carrier.

22. An oral hygiene or consumable product comprising: a compound or product according to any preceding claim.

23. The method of any of the preceding claims, comprising:

separating off the ester, and

reacting the ester and amine to form the menthyl glycinate ester.